In recent years, the FDA has tried to become more transparent in its approval methodology, working closely with industry and investigators to ensure studies follow the correct protocol from the outset. In that regard, an FDA representative, Andrew Farb, MD, last week outlined steps to help streamline the approval process for bioabsorbable stents, at the Cardiovascular Revascularization Therapies (CRT) 2008 meeting in Washington, D.C.

Farb, from the interventional cardiology devices branch at the FDA’s Center for Devices and Radiological Health, said the agency requires answers to the following challenges in the characterization of biodegradable stents (BDS):

• What are the expected advantages of a BDS?
• What is the degradation profile?
• What are the degradation products and what are their biologic activities?
• How does the proposed stent design balance the need for mechanical integrity following deployment with the ability to degrade over time?

The FDA approach to all drug-eluting stents (DES), including BDS, requires regulatory submissions of an investigational device exemption (IDE), which will allow the company to conduct clinical trials in the U.S., and will evaluate the significant risk of the product.

The FDA also requires a premarket approval application for a comprehensive review of bench testing, animal studies, and all clinical data to establish a reasonable assurance of safety and effectiveness—and manufacturing inspection prior to approval.

Preclinical testing objectives for DES include in vitro and in vivo elution of both the coating substrate and the methods and specifications to allow stability, Farb said. Another objective is to have adequate animal studies to assess safety prior to human studies.

Regarding BDS nonclinical bench testing, standard tests such as stent and coating durability are no longer relevant. Tests are still needed, however, for the mechanical properties in a physiologically relevant environment.

Researchers need to conduct mechanical tests at multiple time points to fully characterize the impact of degradation on mechanical integrity, Farb said. They also need to consider the clinical relevance of ‘particulate matter’ when the stent degrades.

For biocompatibility testing in BDS nonclinical evaluation, standard tests may need to be altered in regards to extraction conditions and time exposure. It may also be appropriate to conduct separate testing of degradation products, he said.

When moving to the clinical evaluation stage, researchers must be aware that the novelty of the new BDS components, such as the drug and its release mechanism, stent platform, coating, and polymer, could affect the trial design and sample size.

The FDA recommends a randomized, controlled trial for initial marketing approval for new BDS, comparing the superiority or non-inferiority to approved DES, along with the target lesion failure rates as the primary endpoint with a composite of cardiac death, target vessel myocardial infarction, and target vessel revascularization.

The trial sample size should be large enough to provide adequate power to compare target lesion failure rates between BDS and a control group. Also, the FDA will expect duration of patient follow-up that reflects degradation profile to adequately capture outcomes before, during, and after stent degradation.

Other important clinical assessments for the evaluation of BDS are:

• procedural results, including device success, which includes achievement of an acceptable post-deployment stenosis with the test device alone;
• procedural success, which includes achievement of an acceptable residual stenosis with the test device plus adjunctive procedures and devices; and
• clinical success, which includes device success without in-hospital major adverse cardiac events.

If visibility on fluoroscopy is an issue, researchers would need to assess the frequency of a geographic miss and the ability to accurately deploy overlapping stents in bailout situations, Farb said.

Imaging considerations for clinical BDS evaluation include:

• confirmation of absorption
• documentation of the effects of loss of rigid scaffold on restenosis within the stent and at the edges; and
• changes in stent size, such as shrinkage.

The researchers will also have to answer the question: Is stent mal-apposition relevant for a biodegradable stent?

The final imaging angio/IVUS core lab adjudication may be challenging to identify treatment site when the stent is no longer present, comparing blinding issues in clinical trials to a non-degradable stent, Farb said.

Considerations for BDS clinical program include documenting:

• the total number of patients treated to detect uncommon but clinically important safety events (not all patients need to be part of a randomized trial and researchers can use multiple trials both in and outside the United States);
• patient clinical follow-up through five years;
• rates of stent thrombosis (ARC definitions);
• dual anti-platelet therapy use and optimal duration following BDS implantation; and
• post-approval study with the FDA, which includes pooling of clinical data with pre-market data.

The challenges inherent to BDS add multiple levels of complexity to FDA review, and require additional studies to understand the safety and effectiveness profile, Farb concluded.

“Come early, and come often,” he said, stressing the need to be in league with the FDA regarding BDS development.